Prognostic impact of clinical and radiological factors on leptomeningeal metastasis from solid cancers.

PURPOSE: The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is essential for selecting an appropriate treatment. The European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines for LM proposed a classification based on the cerebrospinal fluid cytological findings and contrast-enhanced magnetic resonance imaging (MRI) pattern. However, few studies have validated the utility of this classification. This study aimed to investigate the prognostic factors of LM, including the radiological and cytological types. METHODS: We retrospectively analyzed the data of 240 adult patients with suspected LM who had undergone lumbar puncture between April 2014 and September 2021. RESULTS: The most common primary cancer types were non-small-cell lung cancer (NSCLC) (143 (60%)) and breast cancer (27 (11%)). Positive cytology results and the presence of leptomeningeal lesions on contrast-enhanced MRI correlated with decreased survival in all patients. Nodular lesions detected on contrast-enhanced magnetic resonance were a poor prognostic factor in cytology-negative patients, while contrast-enhanced patterns had no prognostic significance in cytology-positive patients. Systemic therapy using cytotoxic agents and molecular-targeted therapy after LM diagnosis correlated with prolonged survival, regardless of the cytology results. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment and systemic chemotherapy after LM improved the survival of EGFR-mutated and wild-type NSCLC patients with positive cytology results. CONCLUSIONS: This study validated the efficacy of prognostication according to the EANO-ESMO guidelines for LM. Systemic therapy after LM diagnosis improves the survival of NSCLC patients.

Genome-wide association study on meningioma risk in Japan: a multicenter prospective study.

PURPOSE: Although meningiomas are the most common primary intracranial tumors, their genetic etiologies have not been fully elucidated. To date, only two genome-wide association studies (GWASs) have focused on European ancestries, despite ethnic differences in the incidence of meningiomas. The aim of this study was to conduct the first GWAS of Japanese patients with meningiomas to identify the SNPs associated with meningioma susceptibility. METHODS: In this multicenter prospective case-control study, we studied 401 Japanese patients with meningioma admitted in five institutions in Japan, and 50,876 control participants of Japanese ancestry enrolled in Biobank Japan. RESULTS: The quality control process yielded 536,319 variants and imputation resulted in 8,224,735 variants on the autosomes and 224,820 variants on the X chromosomes. This GWAS eventually revealed no genetic variants with genome-wide significance (P < 5 × 10 - 8) and observed no significant association in the previously reported risk variants rs11012732 and rs2686876 due to low minor allele frequency in the Japanese population. CONCLUSION: This is the first GWAS of meningiomas in East Asian populations and is expected to contribute to the development of GWAS research for meningiomas.

Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

Qualitative MR features to identify non-enhancing tumors within glioblastoma's T2-FLAIR hyperintense lesions.

PURPOSE: To identify qualitative MRI features of non-(contrast)-enhancing tumor (nCET) in glioblastoma's T2-FLAIR hyperintense lesion. METHODS: Thirty-three histologically confirmed glioblastoma patients whose T1-, T2- and contrast-enhanced T1-weighted MRI and 11C-methionine positron emission tomography (Met-PET) were available were included in this study. Met-PET was utilized as a surrogate for tumor burden. Imaging features for identifying nCET were searched by qualitative examination of 156 targets. A new scoring system to identify nCET was established and validated by two independent observers. RESULTS: Three imaging features were found helpful for identifying nCET; "Bulky gray matter involvement", "Around the rim of contrast-enhancement (Around-rim)," and "High-intensity on T1WI and low-intensity on T2WI (HighT1LowT2)" resulting in an nCET score = 2 × Bulky gray matter involvement - 2 × Around-rim + HighT1LowT2 + 2. The nCET score's classification performances of two independent observers measured by AUC were 0.78 and 0.80, with sensitivities and specificities using a threshold of four being 0.443 and 0.771, and 0.916 and 0.768, respectively. The weighted kappa coefficient for the nCET score was 0.946. CONCLUSION: The current investigation demonstrated that qualitative assessments of glioblastoma's MRI might help identify nCET in T2/FLAIR high-intensity lesions. The novel nCET score is expected to aid in expanding treatment targets within the T2/FLAIR high-intensity lesions.

[Astrocytoma, IDH-Mutant].

Astrocytoma, IDH-mutant is defined as infiltrative diffuse glioma harboring IDH1/2 mutation without accompanying 1p/19q codeletion in the current diagnostic system based on the 5th edition of the World Health Organization Classification of Tumors of the Central Nervous System. This revision delineates this neoplasm as a molecularly and clinically relevant tumor type. The evidence for the clinical management of patients with glioma has been largely established based on the results of clinical studies using the diagnostic criteria before the molecular classification. Many clinical studies investigated astrocytoma, IDH-mutant in combination with IDH-wildtype gliomas or oligodendrogliomas. The aim of the present study was to discuss the optimal management of astrocytoma, IDH-mutant based on the growing number of recent clinical studies incorporating molecular analyses. Particularly, the significance of the extent of surgical removal has increased after the definition of this tumor type in comparison with other types of gliomas.

Eribulin prolongs survival in an orthotopic xenograft mouse model of malignant meningioma.

Meningioma is the most common intracranial tumor, with generally favorable patient prognosis. However, patients with malignant meningioma typically experience recurrence, undergo multiple surgical resections, and ultimately have a poor prognosis. Thus far, effective chemotherapy for malignant meningiomas has not been established. We recently reported the efficacy of eribulin (Halaven) for glioblastoma with a telomerase reverse transcriptase (TERT) promoter mutation. This study investigated the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo. Two meningioma cell lines, IOMM-Lee and HKBMM, were used in this study. The strong inhibition of cell proliferation by eribulin via cell cycle arrest was demonstrated through viability assay and flow cytometry. Apoptotic cell death in malignant meningioma cell lines was determined through vital dye assay and immunoblotting. Moreover, a wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. Intraperitoneal administration of eribulin significantly prolonged the survival of orthotopic xenograft mouse models of both malignant meningioma cell lines implanted in the subdural space (P < .0001). Immunohistochemistry confirmed apoptosis in brain tumor tissue treated with eribulin. Overall, these results suggest that eribulin is a potential therapeutic agent for malignant meningiomas.

TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma.

The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 -), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN -) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55-4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN - was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09-5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM.

Characteristics and outcomes of elderly patients with diffuse gliomas: a multi-institutional cohort study by Kansai Molecular Diagnosis Network for CNS Tumors.

INTRODUCTION: This study investigates the current state of clinical practice and molecular analysis for elderly patients with diffuse gliomas and aims to elucidate treatment outcomes and prognostic factors of patients with glioblastomas. METHODS: We collected elderly cases (≥ 70 years) diagnosed with primary diffuse gliomas and enrolled in Kansai Molecular Diagnosis Network for CNS Tumors. Clinical and pathological characteristics were analyzed retrospectively. Various factors were evaluated in univariate and multivariate models to examine their effects on overall survival. RESULTS: Included in the study were 140 elderly patients (WHO grade II: 7, III: 19, IV: 114), median age was 75 years. Sixty-seven patients (47.9%) had preoperative Karnofsky Performance Status score of ≥ 80. All patients underwent resection (gross-total: 20.0%, subtotal: 14.3%, partial: 39.3%, biopsy: 26.4%). Ninety-six of the patients (68.6%) received adjuvant treatment consisting of radiotherapy (RT) with temozolomide (TMZ). Seventy-eight of the patients (75.0%) received radiation dose of ≥ 50 Gy. MGMT promoter was methylated in 68 tumors (48.6%), IDH1/2 was wild-type in 129 tumors (92.1%), and TERT promoter was mutated in 78 of 128 tumors (60.9%). Median progression-free and overall survival of grade IV cases was 8.2 and 13.6 months, respectively. Higher age (≥ 80 years) and TERT promoter mutated were associated with shorter survival. Resection and adjuvant RT + TMZ were identified as independent factors for good prognosis. CONCLUSIONS: This community-based study reveals characteristics and outcomes of elderly glioma patients in a real-world setting. Elderly patients have several potential factors for poor prognosis, but resection followed by RT + TMZ could lengthen duration of survival.

Glioblastomas with IDH1/2 mutations have a short clinical history and have a favorable clinical outcome.

OBJECTIVE: Glioblastomas with isocitrate dehydrogenase 1/2 mutations comprise a biologically distinct subgroup of glioblastomas. We studied isocitrate dehydrogenase 1/2 mutant glioblastomas at the clinical, molecular and radiological levels to define their clinical features, including the prognostic value of isocitrate dehydrogenase 1/2 mutations compared with isocitrate dehydrogenase 1/2 wild-type glioblastomas. METHODS: We investigated 128 newly diagnosed glioblastoma patients who were treated at our institute between January 2005 and May 2013. Isocitrate dehydrogenase 1/2 mutation status was determined using pyrosequencing. O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation and 1p/19q co-deletions were also analyzed using pyrosequencing and multiplex ligation-dependent probe amplification, respectively. RESULTS: Isocitrate dehydrogenase 1/2 mutations were detected in 10 of 128 patients (7.8%). Isocitrate dehydrogenase 1/2 mutations were correlated with a younger age, the presence of an oligodendroglial component and 1p/19q co-deletions and a longer survival time. The interval from initial symptom to initial operation did not differ according to isocitrate dehydrogenase 1/2 mutation status (median interval: 2.3 versus 1.2 months; P = 0.13). Two of three isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions had an oligodendroglial component and were associated with a prolonged survival time. Multivariate analysis of 90 patients treated with temozolomide-based chemoradiotherapy indicated that age, extent of resection, postoperative Karnofsky performance score and O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation were correlated with better survival. Isocitrate dehydrogenase 1/2 mutations showed a trend for improved survival (P = 0.068). CONCLUSIONS: Most isocitrate dehydrogenase 1/2 mutant glioblastomas have a short clinical history, and some isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions behave like oligodendroglial tumors. Isocitrate dehydrogenase 1/2 mutations may have a positive prognostic impact on the Japanese population.

Human chorionic gonadotropin is expressed virtually in all intracranial germ cell tumors.

Human chorionic gonadotropin (hCG) production has been utilized as a diagnostic marker for germinoma with syncytiotrophoblastic giant cells (STGC) and choriocarcinoma. Elevated hCG in germinoma is considered to predict less favorable prognosis, and an intensive treatment strategy may accordingly be applied. However, there is some evidence that any germinoma may produce hCG to varying extent. We investigated mRNA expression of the hCG ß subunit (hCGß) using real time quantitative polymerase chain reaction in 94 germ cell tumors (GCTs). Most (93.3 %) GCTs showed higher expression levels compared with that of normal brain tissue (1.09 × 10(0)-1.40 × 10(5) fold). The expression was the highest in GCTs which harbor choriocarcinoma or STGC components. The expression level of hCGß in germinoma was highly variable (1.09 × 10(0)-5.88 × 10(4) fold) in linear but not bimodal distribution. hCG concentrations in serum and CSF correlated with gene expression, especially when GCTs with single histological component were analyzed separately. The expression was not significantly associated with recurrence in pure germinoma. These results suggest that the serum/CSF hCG levels may need to be interpreted with caution as most GCTs appear to have the capacity of producing hCG irrespective of their histology. The clinical significance of ubiquitous hCG expression in GCTs needs further investigation.

Gsp mutation in acromegaly and its influence on TRH-induced paradoxical GH response.

OBJECTIVE: We recently reported that paradoxical GH response to TRH administration reflects biological characteristics in patients with acromegaly. The aim of this study is to elucidate the relationship between gsp mutations and the paradoxical GH response to TRH. PATIENTS: Sixty-seven patients with acromegaly were included for analysis. Paradoxical increase in serum GH level to TRH, GH suppression by octreotide and bromocriptine, radiological profiles and histopathological findings were analysed with respect to tumour gsp-mutation status. RESULTS: Twenty-six (38·8%) gsp mutations were detected, and the number of paradoxical GH responders to TRH, defined as an increase of 100% or more in GH after TRH, was 49 (73·1%). Among the paradoxical GH responders to TRH, 21 patients (42·9%) had a gsp mutation and 28 patients (57·1%) did not. The percentage of paradoxical GH responders to TRH in gsp-positive and gsp-negative patients was not significantly different (80·8% and 68·3%, respectively). The gsp-positive group showed a significantly higher paradoxical increase in serum GH level by TRH administration (1830% vs 650% GH increase, P = 0·045) and greater GH suppression by octreotide (88·7% vs 75·4% GH decrease, P = 0·003) than the gsp-negative group. CONCLUSION: Paradoxical GH response to TRH was observed regardless of gsp mutation, although the rate of increase was significantly higher in gsp-positive patients. These results suggest that gsp mutation is not sufficient to cause the paradoxical GH response to TRH, while other unidentified factors have a strong influence on paradoxical GH response to TRH in patients with acromegaly.

Risk factors for early death after surgery in patients with brain metastases: reevaluation of the indications for and role of surgery.

Surgical resection remains an important option for the treatment of brain metastases despite recent advancements in radiotherapy and systemic therapy. When selecting surgical candidates, it is important to exclude terminal cases who will receive neither a survival benefit nor an improvement in their quality of life. We reviewed a total of 264 surgical cases of brain metastases and analyzed the clinical characteristics of early death in order to clarify the indication for and the role of surgery. The median survival time (MST) after surgery in all cases was 12.4 months. Early death was defined as death within 6 months, and 23% (62 cases) of this series were succumbed to this. A decrease in postoperative Karnofsky performance status (KPS) (<70) (P = 0.041), lack of systemic therapy after surgery (P < 0.0001), and uncontrolled extracranial malignancies (P = 0.0022) were significantly related to early death in multivariate analysis, while preoperative KPS (<70) and recursive partitioning analysis (RPA) class were related to early death only in univariate analysis (P < 0.05). When analyzing patients with uncontrolled extracranial malignancies and those with a postoperative KPS score of 70 or greater (who were generally candidates for systemic therapy), the MST was significantly longer in the systemic therapy (+) group compared with the systemic therapy (-) group (12.5 vs. 5.6 months; P = 0.0026). Our data indicate that the postoperative RPA class and treatment strategy were associated with early death. Deterioration of patients by surgery should be avoided in the treatment of brain metastases.

Catheter embolization for pulmonary arteriovenous malformations during chemotherapy for appendiceal adenocarcinoma: A case report of associated brain abscess.

Pulmonary arteriovenous malformations are rare, abnormal, low-resistance vascular structures that connect a pulmonary artery to a vein. They are common in patients with hereditary hemorrhagic telangiectasia; however, acquired malformations can occur in patients with underlying diseases such as chest trauma, hepatic cirrhosis, and mitral stenosis. Pulmonary arteriovenous malformations bypass the normal pulmonary capillary bed and result in intrapulmonary right-to-left shunts, which may cause central nervous system complications such as brain abscesses or ischemic stroke. Brain abscesses related to pulmonary arteriovenous malformations are not uncommon; however, reports of their occurrence during chemotherapy are limited. Here, we report the case of a 68-year-old woman with bilateral pulmonary arteriovenous malformations and appendiceal adenocarcinoma who developed a bacterial brain abscess during chemotherapy. The infection was treated using abscess drainage and antibiotic therapy. After the brain abscess healed, catheter embolization was performed on the pulmonary arteriovenous malformations and chemotherapy was resumed. The present case suggests that if a patient with a malignancy has a pulmonary arteriovenous malformation, clinicians should pay special attention to complications such as brain abscesses during chemotherapy. For patients who do not urgently need chemotherapy, embolization of the pulmonary arteriovenous malformation before chemotherapy may be a better treatment option.

Multifraction stereotactic radiotherapy utilizing inhomogeneous dose distribution for brainstem metastases: a single-center retrospective analysis.

Brainstem metastases are challenging to manage owing to the critical neurological structures involved. Although stereotactic radiotherapy (SRT) offers targeted high doses while minimizing damage to adjacent normal tissues, the optimal dose fractionation remains undefined. This study evaluated the efficacy and safety of multifraction SRT with an inhomogeneous dose distribution. This retrospective study included 31 patients who underwent 33 treatments for 35 brainstem lesions using linear accelerator-based multifraction SRT (30 Gy in five fractions, 35 Gy in five fractions or 42 Gy in 10 fractions) with an inhomogeneous dose distribution (median isodose, 51.9%). The outcomes of interest were local failure, toxicity and symptomatic failure. The median follow-up time after brainstem SRT for a lesion was 18.6 months (interquartile range, 10.0-24.3 months; range, 1.8-39.0 months). Grade 2 toxicities were observed in two lesions, and local failure occurred in three lesions. No grade 3 or higher toxicities were observed. The 1-year local and symptomatic failure rates were 8.8 and 16.7%, respectively. Toxicity was observed in two of seven treatments with a gross tumor volume (GTV) greater than 1 cc, whereas no toxicity was observed in treatments with a GTV less than 1 cc. No clear association was observed between the biologically effective dose of the maximum brainstem dose and the occurrence of toxicity. Our findings indicate that multifraction SRT with an inhomogeneous dose distribution offers a favorable balance between local control and toxicity in brainstem metastases. Larger multicenter studies are needed to validate these results and determine the optimal dose fractionation.

Association of increasing gross tumor volume dose with tumor volume reduction and local control in fractionated stereotactic radiosurgery for unresected brain metastases.

BACKGROUND: Fractionated stereotactic radiosurgery (fSRS) is an important treatment strategy for unresected brain metastases. We previously reported that a good volumetric response 6 months after fSRS can be the first step for local control. Few studies have reported the association between gross tumor volume (GTV) dose, volumetric response, and local control in patients treated with the same number of fractions. Therefore, in this study, we aimed to investigate the GTV dose and volumetric response 6 months after fSRS in five daily fractions and identify the predictive GTV dose for local failure (LF) for unresected brain metastasis. METHODS: This retrospective study included 115 patients with 241 unresected brain metastases treated using fSRS in five daily fractions at our hospital between January 2013 and April 2022. The median prescription dose was 35 Gy (range, 30-35 Gy) in five fractions. The median follow-up time after fSRS was 16 months (range, 7-66 months). RESULTS: GTV D80 > 42 Gy and GTV D98 > 39 Gy were prognostic factors for over 65% volume reduction (odds ratio, 3.68, p < 0.01; odds ratio, 4.68, p < 0.01, respectively). GTV D80 > 42 Gy was also a prognostic factor for LF (hazard ratio, 0.37; p = 0.01). CONCLUSIONS: GTV D80 > 42 Gy in five fractions led to better volume reduction and local control. The goal of planning an inhomogeneous dose distribution for fSRS in brain metastases may be to increase the GTV D80 and GTV D98. Further studies on inhomogeneous dose distributions are required.

Prediction of MGMT promotor methylation status in glioblastoma by contrast-enhanced T1-weighted intensity image.

Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images. Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status. Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory (p = .015, odds ratio = 2.44) and for the validation cohort (p = .006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort. Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status.

Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort.

This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term "midline" areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4-78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9-11.9, 95% CI) and 16.6 ± 1.4 (13.9-19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma.

Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss.

Telomere lengthening is one of the key events in most cancers, and depends largely on telomerase activation. Telomerase activation is a well-known phenomenon in gliomas; however, its mechanism remains obscure. In this study, we investigated the presence of mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in a series of 546 gliomas. We found a high incidence of mutually exclusive mutations located at two hot spots, C228T and C250T, in all subtypes of gliomas (55 %). The frequency of mutation was particularly high among primary glioblastomas (70 %) and pure oligodendroglial tumors (74 %), while relatively low in diffuse astrocytomas and anaplastic astrocytomas (19 and 25 %, respectively). The expression level of TERT in tumors carrying those mutations was on average 6.1 times higher than that of wild-type tumors, indicating that the mutated promoter leads to upregulation of TERT. TERT promoter mutations were observed in almost all tumors harboring concurrent total 1p19q loss and IDH1/2 mutations (98 %). Otherwise TERT promoter mutations were mostly observed among IDH wild-type tumors. Most EGFR amplifications (92 %) were also associated with TERT promoter mutations. Our data indicate that mutation of the TERT promoter is one of the major mechanisms of telomerase activation in gliomas. The unique pattern of TERT promoter mutations in relation to other genetic alterations suggests that they play distinct roles in the pathogenesis of oligodendroglial and astrocytic tumors. Our results shed a new light on the role of telomerase activation in the development of adult gliomas.

Prevalence of cerebral aneurysm in patients with acromegaly.

The prevalence of cerebral aneurysm was retrospectively investigated in 208 patients with acromegaly relative to the rate of cerebral aneurysm in a group of control subjects. Neuroradiological examinations of the cerebral vascular system were conducted in 208 acromegaly patients (101 men; mean age, 48.8 years). The prevalence of cerebral aneurysm in the acromegaly patients was compared to that in a control group consisting of 7,390 subjects who underwent "brain checkup" between 2006 and 2008 (mean age, 51.6 years). In the acromegaly group, cerebral aneurysm was detected in 4.3 % of patients. By sex, the prevalence was 6.9 % in males, a significantly proportion than that in the control group with an odds ratio of 4.40. The prevalence in females did not differ between the two groups. In the acromegaly group, the rate of hypertension was significantly higher in the patients with aneurysm compared to those without aneurysm. Multiple logistic regression identified acromegaly as a significant factor related to the prevalence of cerebral aneurysm in all male subjects; other factors, such as age, hypertension and smoking, were not found to be significant. A significantly higher prevalence of cerebral aneurysm was detected in male patients with acromegaly. This finding indicates that excess growth hormone or insulin-like growth factor 1 affects the cerebral vascular wall, resulting in aneurysm formation. In addition to known systematic complications in the cardiovascular, respiratory, metabolic, and other systems, the risk of cerebral aneurysm should be considered in the management of acromegaly.

Management of glioblastoma in an NF1 patient with moyamoya syndrome: a case report.

INTRODUCTION: Glioma and moyamoya syndrome are both potential complications of neurofibromatosis type 1 (NF1). Here, we report the first case of NF1 concomitantly presenting with glioblastoma 10 years after surgical treatment of moyamoya syndrome. CASE REPORT: A 14-year-old boy with NF1 was incidentally diagnosed by magnetic resonance imaging (MRI) with a thalamic tumor during a follow-up for moyamoya syndrome, which had been treated with surgery 10 years earlier. After observation for 36 months, he developed left hemiparesis, and MRI revealed an increase in tumor size and obstructive hydrocephalus due to the tumor. Needle biopsy was performed through small craniotomy, and the histological diagnosis was glioblastoma. After concurrent chemoradiotherapy with 23 cycles of temozolomide, partial response of the tumor was observed. However, 24 months after the start of the initial therapy, the tumor showed regrowth, and the patient died 30 months after the initial therapy. No cerebrovascular events associated with moyamoya syndrome and chemoradiotherapy were observed during the clinical course of glioblastoma. DISCUSSION: Glioblastoma is a fatal disease in children, and our patient successfully received chemoradiotherapy with temozolomide despite the diagnoses of NF1 and moyamoya syndrome. Although radiotherapy or chemotherapy potentially causes cerebrovascular complications, chemoradiotherapy might be feasible for glioblastoma treatment in patients with moyamoya syndrome and NF1. The following issues are discussed in the management of the present case: the indication of biopsy in NF1 cases, the method of surgery, and the treatment protocol for tumors concomitant with moyamoya disease or syndrome.